Alzheimer's disease (AD) is characterized by the presence of numerous neuritic plaques, neurofibrillary tangles, and neuronal loss. The plaques, mainly composed of β-amyloid (Aβ) peptide fragments, are derived from the processing of amyloid precursor protein (APP) by β- and γ-secretases. The presence of reactive microglia, astrocytes, and complement factors associated with the fibrillar Aβ plaques suggests the development of a local and chronic inflammatory response within the plaque area and is consistent with the hypothesis that complement activation contributes to this inflammatory process. In AD brains, C1q, the first component of the classical complement pathway that binds fibrillar Aβ and activates complement, has been shown to be associated with fibrillar Aβ plaques. Other complement proteins have also been detected in the plaque area, and their synthesis has been shown to occur within the AD brain.
Aggregation and deposition of amyloid β-protein (Aβ or beta amyloid) is considered to be a primary pathological event in Alzheimer's disease (AD). The longer 42-43 amino acid Aβ forms have been implicated in the formation of amyloid plaques, the aggregation state of the peptide is critical in determining its neurotoxicity. Many different forms of Aβ have been identified and characterized including fibrils, proto-fibrils, annular structures, globular structures, amorphous aggregates and various soluble oligomers. Numerous studies indicate that small oligomeric morphologies of Aβ are the primary toxic species in AD. These small oligomers are also called “low-n oligomers” (i.e., dimers, trimers, or tetramers).
Accordingly, there exists the need for new therapies and reagents for the treatment of Alzheimer's disease, in particular, therapies and reagents capable of effecting a therapeutic and diagnostic benefit at physiologic (e.g., non-toxic) doses.